Currently, there is no effective, safe clinical treatment for sepsis, which accounts for 9.3% of the overall deaths in the United States annually. Sepsis is not only related to infections. Shock, trauma, hemorrhage, and other conditions of critical care contribute to severe sepsis, which is characterized by an overwhelming systemic inflammatory response that causes lethal multiple organ failure. Our goal is to develop novel therapeutic strategies to restrain systemic inflammation and improve survival in experimental sepsis. Treatment with cholinergic agonists such as nicotine, started one day after the onset of the disease, also attenuate systemic inflammation and rescue mice from established sepsis both in lethal endotoxemia and cecal ligation and puncture. Nicotine has been already used in clinical trials for inflammatory disorders such as ulcerative colitis, but the therapeutic potential of this mechanism is underestimated due to the collateral toxicity of nicotine. There are two fundamental considerations limiting the translational potential of this mechanism in critical care: (1) identification of the specific receptor(s) involved in the process; and (2) identification of the mechanism inhibiting the production of cytokines and pathological markers associated with sepsis. Our studies in RAW264.7 macrophage-like cells indicate that cholinergic agonists inhibit the production of proinflammartory cytokines by modulating NF-kB through a mechanism dependent on the alpha7 nicotinic acethlcholine receptor (nAChR). Since our most recent studies indicate that nicotine attenuates systemic inflammation and improves survival in sham but not in splenectomized mice, we propose to study the implications of these two factors in the spleen. Our objectives are to determine whether cholinergic agonists inhibit a specific step of the NF-kB pathway in the spleen and whether cholinergic agonists modulate NF-kB in the spleen through a mechanism mediated by the alpha7nAChR. If so, specific alpha7nAChR-agonists may represent a promising pharmacological strategy to avoid the toxicity of nicotine and modulate NF-kB in specific immune cells during infectious and inflammatory disorders. PUBLIC HEALTH RELEVANCE Currently, there is no effective, safe clinical treatment for sepsis, which accounts for 9.3% of the overall deaths in the United States annually. Our goal is to determine the molecular mechanism by which cholinergic agonists restrain systemic inflammation in sepsis. These studies will allow the design of novel pharmacological strategies to improve survival in sepsis